Steryl magnesium halide and process for producing the same



Patented Sept. 9, 1941 STERYL MAGNESIUM HALIDE AND PROCESS FOR PRODUCING THE SAME amen Earl Marker, State College, 1a., assign Company, Detroit, Mich,

to Parke, Davis & corporation of Mic No Drawing. Application March 4, 1938, Serial No. 194,013

The invention relates to new steryl magnesium halides and a process for their preparation.

The present invention is a continuation in part of my application, Serial No. 4,223, filed April 13, 1936.

One of the objects is to obtain a new class of compounds which may be broadly designated as steryl magnesium halides. One of the features of my invention is the discovery that a sterol halide can be reacted with magnesium to convert it into its Grignard compound, that is, a compound of the type R-Mg-X where R represents the radical of a sterol hydrocarbon such as the cholesteryl radical, C27H45, and X is a. halogen atom.

My invention not only includes the preparation of cholesteryl magnesium halides but also includes reacting substituted as well as unsubstituted steryl halides. It is obvious, however, that in the present invention those substituted steryl halides are excluded wherein the substituent other than the halogen atom would react with magnesium,or the steryl magnesium halide being produced, or otherwise interfere with the desired production of a steryl magnesium halide derivative.

Hydroxyl, aldehyde, ketone, carboxylic and like groups which are reactive toward steryl magnesium; halides are examples of substituents which are excluded, while alkyl, aryl, alicyclic and similar unreactive groups do not interfere when present as substituen in the steryl halide compounds to be reacted uh magnesium. Furthermore, the carbocyclic rings of the sterol nucleus may or may not contain unsaturated car- I bon-to-carbon doublebonds.

All of the new compounds have a sterol carhon skeleton of l'l-carbon atoms attached to'the group, -MgX.. The sterol skeleton can trated as follows:

In general, the steryl halide compounds described above, which are suitable for reaction beillus- 45 solvent in which they were produced as dry solid compomtions. However,

a Claims. (cl. zoo-397.2)

with magnesium to form the corresponding steryl magnesium halide, may be represented by the formula CH: R

where X is a halogen atom replacing a hydrogen atom attached to one of the carbocyclic carbon atoms and R is a hydrocarbon side-chain. Other groups which are unreactive, such as those mentioned above, may also be present as substituents in these compounds, in addition to the halogen, X, and such compounds are included hereinafter and in the appended claims by the expression, "steryl halide." Thus it is obvious that the term stery is intended to indicate a dimethyl cyclopentano polyhydrophenanthrene hydrocarbon radical having a side chain at the number 17 carbon atom.

The steryl magnesium halide compounds of the present invention are valuable intermediates in the chemistry of sterols and sterol derivatives and are often useful in the synthesis of compounds having characteristic physiological properties and therapeutic usefulness.

Steryl magnesium halide compounds are particularly useful intermediates, because they are capable of reacting withwater or with the other compounds generally used for decomposing the so-called Grignard compounds to eliminate magnesium. The reaction products thereby obtained are often racemic mixtures in which a new chemspatial arrangement which is that originally present.

ical group has replaced the original halide atom of the steryl halide, the new group having a the opposite of The steryl magnesium halide compounds may be isolated from.the solutions in inert organic in such form they are not convenient to handle and, for practical purposes, the preferred compositions oi the invention are those in which the steryl magnesium ether. However, other equivalent organic solvents, such as other ethers, hydrocarbons, anisole, benzol, phenetol, toluene, and the like, may be used The invention may be illustrated by the m1- lowing examples: EXAMPLE 1.-Preparation of cholesteryl magnesium chloride 10.2 grams of magnesium turnings are covered with 50 cc. of dry ether. One cc. of ethyl bromide is added to this mixture of ether and magnesium to assist in initiating the reaction between the magnesium and the cholesteryl chloride to be addedlater. After the reaction between the ethyl bromide and the magnesium has started, a solution of 1'70 grams of well-purified cholesteryl chloride in one liter of dry ether is added to the reaction mixture dropwise with vigorous stirring over a period of six hours. The ether solution is kept at reflux temperature during the addition of cholesteryl chloride. After the cholesteryl chloride is all added, the mixture is stirred vigorously for several hours. At the end of this time the magnesium is in solution, and the product consists of a substantially pure ethereal solution or suspension of cholesteryl magnesium chloride.

If sufllcient solvent is present, either before or after the reaction of the magnesium, all of the cholesteryl magnesium chloride goes into solution. However, the presence in the solution of excess of undissolved cholesteryl magnesium halide does not interfere with the utility of such mixtures for further reaction.

The cholesteryl magnesium chloride can be used either in the form of the ether solution or suspension obtained, or the solvent can be evaporated, preferably in vacuo at low temperature,

to leave a solid white residue of cholesteryl magnesium chloride. When making up the solid dry product for use, it can be taken up in ethyl ether or other suitable solvent.

The product of this example may be represented by the following formula:

CH: Cu: Cal

cholesteryl magnesium cluorido Exmmt 2.--Preparation of epi-cholesteryl maynesium chloride 2 or 3 cc. of ethyl bromide are added to a mixture of 51 grams of magnesium turnings and 250 cc. of dry ether. After the reaction of the magnesium with the ethyl bromide has begun, a solution of 850 grams of pure epi-cholesteryl chloride dissolved in flve liters of dry ether is added very slowly with vigorous stirring over a period of six hours. The epi-cholesteryl chloride used in this example can be obtained as described in J. Am. Chem. Soc. 58: 481-483, 1936,

or by any other suitable known method. Durthe form of an amorphous white or slightly graycolored solid by removing the solvent. The product of this example may be represented by the following formula:

GE CaHn Eptcholesteryl magnesium chloride EXAMPLE 3.Preparation of sitosteryl magnesium chloride 19.8 grams of carefully purified sitosteryl chloride, J. Am. Chem. Soc. 59: 2711, 1937, dissolved in 200 cc. of dry ether, are dropped onto two grams of magnesium metal with vigorous stirring. If the reaction of the magnesium with the sitosteryl chloride does not begin readily, it can be started by adding several drops of ethyl bromide. The sitosteryl chloride is added over a period of four hours, after which the mixture is stirred and refluxed overnight or somewhat longer if necessary. Any unchanged magnesium can then be filtered off in an inert atmosphere. Before filtering, however, it is preferable to add enough dry ether to put any undissolved sitosteryl magnesium chloride into solution. The product obtained is an anhydrous ether solution of sitosteryl magnesium chloride. The ether can be removed-as in the preceding examples and solid amorphous white sitosteryl magnesium chloride is obtained.

Cu n sitosteryl magnesium chloride Exunu: 4.--Preparation of stigmasteryl meanesium chloride 22 grams of pure stigmasteryl chloride in 200 cc. of dry ether are added over a period of four hours to a well-stirred mixture of two grams of magnesium, 10 drops of ethyl bromide and 10 cc. of dry ether. The mixture is stirred and refluxed for 20 hours. The reaction mixture is treated for separation of unchanged magnesium as given above for example 3 and a solution of stigmasteryl magnesium chloride in ether is thereby obtained. By removing the ether, solid amorphous grayish CH3 C 1.

Stigmasteryl magnesium chloride In carrying out the examples given, the steryl bromides or iodides can be used, as well as the chlorides, for reaction with magnesium metal. Instead of using ethyl bromide to initiate reaction with magnesium, any other suitable compound may be used, such as methyl iodide, ethyl iodide, ethyl chloride, iodine, various lower alkyl halides, etc.

The steryl magnesium halide compounds are prone to oxidation and are quickly decomposed in presence of moisture, ammonia, carbon dioxide, and other reactive substances. They can be produced by reacting magnuium, as illustrated in the examples, with the halides produced by replacing the hydroxyl of sterols with halogen. For example, phosphorous halides, thionyl halides and like halogenating agents can be reacted with dihydrocholesterol, coprosterol, ostreasterol, ergosterol, cinchol, fucosterol, zymosterol, 4-cholestanol, 7-hydroxy cholestane, ergostanol, 7-dehydrocholesterol, neoergosterol, and various other substituted and unsubstituted hydroxysterol compounds, to give the corresponding derivative in which the hydroxyl is replaced by halogen. These steryl halide compounds are then reacted with magnesium to give steryl magnesium halide compounds.

Numerous hydrocarbon halides, especially those of higher molecular weight, are known to be so unreactive toward magnesium that for practical purposes the yields of organo-magnesium halide are negligible. The steryl halides were found to be of this type.

What I claim as my invention is:

1. A steryl magnesium halide.

2. A steryl magnesium chloride.

3. Cholesteryl magnesium halide.

4. Sitosteryl magnesium halide.

5. Stigmasteryl magnesium halide.

6. Cholesteryl magnesium chloride.

7. A product having the formula C H] CH1 R X-Ms where X is halogen and R is a hydrocarbon sidechain. 

